Cyclopropanecarboxamide-containing compounds and application thereof

Abstract

The present application relates to the field of pharmaceutical chemistry, and specifically to cyclopropanecarboxamide-containing compounds of formula (I) and application thereof. The cyclopropanecarboxamide-containing compounds have great medical value and market potential for autoimmune diseases and myeloproliferative neoplasm diseases.

1 . A compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         Ar is selected from 
       
       
         
           
           
               
               
           
         
          wherein: 
         m is an integer from 1-4; 
         W 1  is selected from 
       
       
         
           
           
               
               
           
         
         W 2  is selected from 
       
       
         
           
           
               
               
           
         
         R is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or halogen; 
         Z 1 , Z 2  and Z 3  are each independently selected from —C(R 3 R 4 )—, —S(O) 2 —, —S(O)—, —CH(S(O) 2 R′)—, or —CH(S(O) 2 NR′R″)—; 
         R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl; 
         R′ and R″ are each independently selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 ; 
         R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         2 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 , having a structure of formula (II): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         m is an integer from 1-4; 
         W 1  is selected from 
       
       
         
           
           
               
               
           
         
         R is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or halogen; 
         Z 1 , Z 2  and Z 3  are each independently selected from —C(R 3 R 4 )—, —S(O) 2 —, —S(O)—, —CH(S(O) 2 R′)—, or —CH(S(O) 2 NR′R″)—, and when Y is hydrogen, Z 2  is not —S(O) 2 —; 
         R′ and R″ are each independently selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 ; 
         R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         3 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 , having a structure of formula (III): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         W 2  is selected from 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl; 
         R′ is selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 . 
       
     
     
         4 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 2 , having a structure of formula (IV): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         m is an integer from 1-4; 
         R is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or halogen; 
         Z 1  is selected from —C(R 3 R 4 )—, —S(O) 2 —, —S(O)—, —CH(S(O) 2 R′)— or —CH(S(O) 2 NR′R″)—; 
         R′ and R″ are each independently selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl and N(C 1 -C 6  alkyl) 2 ; 
         R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         5 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 2 , having a structure of formula (V): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         m is an integer from 1-4; 
         R is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or halogen; 
         Z 2  is selected from —C(R 3 R 4 )—, —S(O) 2 —, —S(O)—, —CH(S(O) 2 R′)—, or —CH(S(O) 2 NR′R″)—, and when Y is hydrogen, Z 2  is not —S(O) 2 —; 
         R′ and R″ are each independently selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 ; 
         R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         6 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 2 , having a structure of formula (VI): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         m is an integer from 1-4; 
         R is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or halogen; 
         Z 3  is selected from —C(R 3 R 4 )—, —S(O) 2 —, —S(O)—, —CH(S(O) 2 R′)—, or —CH(S(O) 2 NR′R″)—; 
         R′ and R″ are each independently selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 ; 
         R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         7 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 3 , having a structure of formula (VII): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl. 
       
     
     
         8 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 3 , having a structure of formula (VIII): 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from —CH or N; 
         Y is selected from hydrogen or halogen, and n is 1 or 2; 
         R′ is selected from substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl, and N(C 1 -C 6  alkyl) 2 . 
       
     
     
         9 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein Y is selected from H or F. 
     
     
         10 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       in the formulas is selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 4 , wherein, in formula (IV), Z 1  is selected from —CH(SO 2 R′), R′ is selected from unsubstituted C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl; R is selected from hydrogen, methyl, methoxy, or halogen. 
     
     
         12 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 5 , wherein, in formula (V), when Y is hydrogen, Z 2  is selected from —CR 3 R 4 — or —CH(S(O) 2 R′)—, and further, wherein, R 3  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 7  cycloalkyl, R′ is selected from C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, R is selected from hydrogen, methyl, methoxy, or halogen; when Y is halogen, Z 2  is selected from —SO 2 —, and R is selected from hydrogen, methyl, methoxy, or halogen. 
     
     
         13 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 6 , wherein, in formula (VI), Z 3  is selected from —SO 2 — or —S(O)—; R is selected from hydrogen, methyl, methoxy, or halogen. 
     
     
         14 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 7 , wherein, in formula (VII), R 1  and R 2  are each independently selected from hydrogen, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, trifluoromethyl, cyclopropyl, or cyclopentyl. 
     
     
         15 . The compound of formula (I), the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 8 , wherein, in formula (VIII), R′ is selected from substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, cyclopropyl, or cyclopentyl, the substituent is selected from the group consisting of: halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl, hydroxyl, amino, NHC 1 -C 6  alkyl and N(C 1 -C 6  alkyl) 2 . 
     
     
         16 . Compounds of the following formulas, stereoisomers or pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . Compounds of the following formulas, stereoisomers or pharmaceutically acceptable salts hereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A pharmaceutical composition, comprising a therapeutically effective amount of the compound, the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for treating a disease associated with abnormal JAK signaling pathway in a subject in need thereof, which comprises a step of administering a therapeutically effective amount of the compound, the stereoisomer, or the pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         20 . The method according to  claim 19 , wherein the disease is an autoimmune disease;
 preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, atopic dermatitis, or systemic lupus erythematosus.   
     
     
         21 . The method according to  claim 19 , wherein the disease is a myeloproliferative neoplasm disease;
 preferably, the myeloproliferative neoplasm disease is selected from essential thrombocytosis, polycythemia vera, or primary myelofibrosis diseases.   
     
     
         22 . A method for treating a disease associated with abnormal JAK signaling pathway in a subject in need thereof, which comprises a step of administering a therapeutically effective amount of the pharmaceutical composition according to  claim 18  to the subject. 
     
     
         23 . The method according to  claim 22 , wherein the disease is an autoimmune disease;
 preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, atopic dermatitis, or systemic lupus erythematosus.   
     
     
         24 . The method according to  claim 22 , wherein the disease is a myeloproliferative neoplasm disease;
 preferably, the myeloproliferative neoplasm disease is selected from essential thrombocytosis, polycythemia vera, or primary myelofibrosis diseases.